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- Patient Information:
Details with Side Effects
Increased Risk of Cardiovascular Mortality for Sulfonylurea Drugs
The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the trial conducted by the University Group Diabetes Program (UGDP), a long-term, prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The trial involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes 1970;19[Suppl. 2]:747-830). UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2Vi times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the trial to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP trial provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glimepiride-containing tablets and of alternative modes of therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was included in this trial, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.
Cardiac Failure With Rosiglitazone
Rosiglitazone, like other thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Patients should be observed for signs and symptoms of heart failure. If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of rosiglitazone must be considered [see BOXED WARNING].
Patients with congestive heart failure (CHF) NYHA Class I and II treated with rosiglitazone have an increased risk of cardiovascular events. A 52-week, double-blind, placebo-controlled echocardiographic trial was conducted in 224 patients with type 2 diabetes mellitus and NYHA Class I or II CHF (ejection fraction ≤45%) on background antidiabetic and CHF therapy. An independent committee conducted a blinded evaluation of fluid-related events (including congestive heart failure) and cardiovascular hospitalizations according to predefined criteria (adjudication). Separate from the adjudication, other cardiovascular adverse events were reported by investigators. Although no treatment difference in change from baseline of ejection fractions was observed, more cardiovascular adverse events were observed with rosiglitazone treatment compared to placebo during the 52-week trial. (See Table 1.)
Table 1. Emergent Cardiovascular Adverse Events in Patients
With Congestive Heart Failure (NYHA Class I and II) Treated With Rosiglitazone
or Placebo (in Addition to Background Antidiabetic and CHF Therapy)
|Cardiovascular deaths||5 (5%)||4 (4%)|
|CHF worsening||7 (6%)||4 (4%)|
|- with overnight hospitalization||5 (5%)||4 (4%)|
|- without overnight hospitalization||2 (2%)||0 (0%)|
|New or worsening edema||28 (25%)||10 (9%)|
|New or worsening dyspnea||29 (26%)||19 (17%)|
|Increases in CHF medication||36 (33%)||20(18%)|
|Cardiovascular hospitalizationa||21 (19%)||15 (13%)|
|Ischemic adverse events||10 (9%)||5 (4%)|
|- Myocardial infarction||5 (5%)||2 (2%)|
|-Angina||6 (5%)||3 (3%)|
|a Includes hospitalization for any cardiovascular reason.|
Initiation of AVANDARYL in patients with established NYHA Class III or IV heart failure is contraindicated. AVANDARYL is not recommended in patients with symptomatic heart failure. [See BOXED WARNING.]
Patients experiencing acute coronary syndromes have not been studied in controlled clinical trials. In view of the potential for development of heart failure in patients having an acute coronary event, initiation of AVANDARYL is not recommended for patients experiencing an acute coronary event, and discontinuation of AVANDARYL during this acute phase should be considered.
Patients with NYHA Class III and IV cardiac status (with or without CHF) have not been studied in controlled clinical trials. AVANDARYL is not recommended in patients with NYHA Class III and IV cardiac status.
Congestive Heart Failure During Coadministration of Rosiglitazone With Insulin: In trials in which rosiglitazone was added to insulin, rosiglitazone increased the risk of congestive heart failure. Coadministration of rosiglitazone and insulin is not recommended. [See INDICATIONS]
In 7 controlled, randomized, double-blind trials which had durations from 16 to 26 weeks and which were included in a meta-analysis1, patients with type 2 diabetes mellitus were randomized to Coadministration of rosiglitazone and insulin (N = 1,018) or insulin (N = 815). In these 7 trials, rosiglitazone was added to insulin. These trials included patients with long-standing diabetes (median duration of 12 years) and a high prevalence of pre-existing medical conditions, including peripheral neuropathy, retinopathy, ischemic heart disease, vascular disease, and congestive heart failure. The total number of patients with emergent congestive heart failure was 23 (2.3%) and 8 (1.0%) in the rosiglitazone plus insulin and insulin groups, respectively.
Heart Failure in Observational Studies of Elderly Diabetic Patients Comparing Rosiglitazone to Pioglitazone: Three observational studies2,4 in elderly diabetic patients (age 65 years and older) found that rosiglitazone statistically significantly increased the risk of hospitalized heart failure compared to use of pioglitazone. One other observational study5 in patients with a mean age of 54 years, which also included an analysis in a subpopulation of patients >65 years of age, found no statistically significant increase in emergency department visits or hospitalization for heart failure in patients treated with rosiglitazone compared to pioglitazone in the older subgroup.
Major Adverse Cardiovascular Events
Cardiovascular adverse events have been evaluated in a meta-analysis of 52 clinical trials, in long-term, prospective, randomized, controlled trials, and in observational studies.
Meta-Analysis of Major Adverse Cardiovascular Events in a Group of 52 Clinical Trials: A meta-analysis was conducted retrospectively to assess cardiovascular adverse events reported across 52 double-blind, randomized, controlled clinical trials (mean duration 6 months).1 These trials had been conducted to assess glucose-lowering efficacy in type 2 diabetes. Prospectively planned adjudication of cardiovascular events did not occur in most of the trials. Some trials were placebo-controlled and some used active oral antidiabetic drugs as controls. Placebo-controlled trials included monotherapy trials (monotherapy with rosiglitazone versus placebo monotherapy) and add-on trials (rosiglitazone or placebo, added to sulfonylurea, metformin, or insulin). Active control trials included monotherapy trials (monotherapy with rosiglitazone versus sulfonylurea or metformin monotherapy) and add-on trials (rosiglitazone plus sulfonylurea or rosiglitazone plus metformin, versus sulfonylurea plus metformin). A total of 16,995 patients were included (10,039 in treatment groups containing rosiglitazone, 6,956 in comparator groups), with 5,167 patient-years of exposure to rosiglitazone and 3,637 patient-years of exposure to comparator. Cardiovascular events occurred more frequently for patients who received rosiglitazone than for patients who received comparators (see Table 2).
Table 2. Occurrence of Cardiovascular Events in a Meta-Analysis
of 52 Clinical Trials
|MACE (a composite of myocardial infarction, cardiovascular death, or stroke)||70 (0.7)||39 (0.6)|
|Myocardial Infarction||45 (0.4)||20 (0.3)|
|Cardiovascular Death||17 (0.2)||9(0.1)|
|All-cause Death||29 (0.3)||17 (0.2)|
|a Events are not exclusive: i.e., a patient with a cardiovascular death due to a myocardial infarction would be counted in 4 event categories (myocardial infarction; myocardial infarction, cardiovascular death, or stroke; cardiovascular death; all-cause death).|
In this analysis, a statistically significant increased risk of myocardial infarction with rosiglitazone versus pooled comparators was observed. Analyses were performed using a composite of major adverse cardiovascular events (myocardial infarction, stroke, and cardiovascular death), referred to hereafter as MACE. Rosiglitazone had a statistically nonsignificant increased risk of MACE compared to the pooled comparators. A statistically significant increased risk of myocardial infarction and statistically non-significant increased risk of MACE with rosiglitazone was observed in the placebo-controlled trials. In the active-controlled trials, there was no increased risk of myocardial infarction or MACE. (See Figure 1 and Table 3.)
Figure 1. Forest Plot of Odds Ratios (95% Confidence Intervals)
for MACE and Myocardial Infarction in the Meta-Analysis of 52 Clinical Trials
Table 3. Occurrence of MACE and Myocardial Infarction in
a Meta-Analysis of 52 Clinical Trials by Trial Type
|N||n (%)|| OR
|Active-Controlled Trials||RSG||2,119||16 (0.8%)|| 1.05
|10 (0.5%)|| 1.00
|Control||1,918||14 (0.7%)||9 (0.5%)|
|Placebo-Controlled Trials||RSG||8,124||54 (0.7%)|| 1.53
|35 (0.4%)|| 2.23
|Placebo||5,636||28 (0.5%)||13 (0.2%)|
|Overall||RSG||10,039||70 (0.7%)|| 1.44
|45 (0.4%)|| 1.8
|Control||6,956||39 (0.6%)||20 (0.3%)|
|RSG = rosiglitazone|
Of the placebo-controlled trials in the meta-analysis, 7 trials had patients randomized to rosiglitazone plus insulin or insulin. There were more patients in the rosiglitazone plus insulin group compared to the insulin group with myocardial infarctions, MACE, cardiovascular deaths, and all-cause deaths (see Table 4). The total number of patients with stroke was 5 (0.5%) and 4 (0.5%) in the rosiglitazone plus insulin and insulin groups, respectively. The use of rosiglitazone in combination with insulin may increase the risk of myocardial infarction.
Table 4. Occurrence of Cardiovascular Events for Rosiglitazone
in Combination With Insulin in a Meta-Analysis of 52 Clinical Trials
(N = 815)
|MACE (a composite of myocardial infarction, cardiovascular death, or stroke)||1.3||0.6|| 2.14
|Myocardial infarction||0.6||0.1|| 5.6
|Cardiovascular death||0.4||0.0|| ND,
|All cause death||0.6||0.2|| 2.19
| ND = not defined
a Events are not exclusive: i.e., a patient with a cardiovascular death due to a myocardial infarction would be counted in 4 event categories (myocardial infarction; myocardial infarction, cardiovascular death, or stroke; cardiovascular death; all-cause death).
Myocardial Infarction Events in Large, Long-Term, Prospective, Randomized, Controlled Trials of Rosiglitazone: Data from 3 large, long-term, prospective, randomized, controlled clinical trials of rosiglitazone were assessed separately from the meta-analysis.6-8 These 3 trials included a total of 14,067 patients (treatment groups containing rosiglitazone N = 6,311; comparator groups N = 7,756), with patient-year exposure of 24,534 patient-years for rosiglitazone and 28,882 patient-years for comparator. Patient populations in the trials included patients with impaired glucose tolerance, patients with type 2 diabetes who were initiating oral agent monotherapy, and patients with type 2 diabetes who had failed monotherapy and were initiating dual oral agent therapy. Duration of follow-up exceeded 3 years in each trial.
In each of these trials, there was a statistically non-significant increase in the risk of myocardial infarction for rosiglitazone versus comparator medications.
In a long-term, randomized, placebo-controlled, 2x2 factorial trial intended to evaluate rosiglitazone, and separately ramipril (an angiotensin converting enzyme inhibitor [ACEI]), on progression to overt diabetes in 5,269 subjects with glucose intolerance, the incidence of myocardial infarction was higher in the subset of subjects who received rosiglitazone in combination with ramipril than among subjects who received ramipril alone but not in the subset of subjects who received rosiglitazone alone compared to placebo.6 The higher incidence of myocardial infarction among subjects who received rosiglitazone in combination with ramipril was not confirmed in the two other large (total N = 8,798) long-term, randomized, active-controlled clinical trials conducted in patients with type 2 diabetes, in which 30% and 40% of patients in the two trials reported angiotensin-converting enzyme inhibitor use at baseline.7,8
There have been no adequately designed clinical trials directly comparing rosiglitazone to pioglitazone on cardiovascular risks. However, in a long-term, randomized, placebo-controlled cardiovascular outcomes trial comparing pioglitazone to placebo in patients with type 2 diabetes mellitus and prior macrovascular disease, pioglitazone was not associated with an increased risk of myocardial infarction or total mortality.9
The increased risk of myocardial infarction observed in the meta-analysis and large, long-term controlled clinical trials, and the increased risk of MACE observed in the meta-analysis described above, have not translated into a consistent finding of excess mortality from controlled clinical trials or observational studies. Clinical trials have not shown any difference between rosiglitazone and comparator medications in overall mortality or CV-related mortality.
Mortality in Observational Studies of Rosiglitazone Compared to Pioglitazone: Three observational studies in elderly diabetic patients (age 65 years and older) found that rosiglitazone statistically significantly increased the risk of all-cause mortality compared to use of ACTOS (pioglitazone).2-4 One observational study5 in patients with a mean age of 54 years found no difference in all-cause mortality between patients treated with rosiglitazone compared to ACTOS (pioglitazone) and reported similar results in the subpopulation of patients >65 years of age. One additional small, prospective, observational study10 found no statistically significant differences for CV mortality and all-cause mortality in patients treated with rosiglitazone compared to ACTOS (pioglitazone).
Rosiglitazone REMS (Risk Evaluation and Mitigation Strategy) Program
Because of the potential increased risk of myocardial infarction, AVANDARYL is available only through a restricted distribution program called the AVANDIA-Rosiglitazone Medicines Access Program [see INDICATIONS]. Both prescribers and patients must enroll in the program to be able to prescribe or receive AVANDARYL, respectively. AVANDARYL will be available only from specially certified pharmacies participating in the program. As part of the program, prescribers will be educated about the potential increased risk of myocardial infarction and the need to limit the use of AVANDARYL to eligible patients. Prescribers will need to discuss with patients the risks and benefits of taking AVANDARYL. To enroll, call 1-800-AVANDIA or visit www.AVANDIA.com.
AVANDARYL is a combination tablet containing rosiglitazone and glimepiride, a sulfonylurea. All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Elderly patients are particularly susceptible to hypoglycemic action of glucose-lowering drugs. Debilitated or malnourished patients, and those with adrenal, pituitary, renal, or hepatic insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. A starting dose of 1 mg glimepiride, as contained in AVANDARYL 4 mg/1 mg, followed by appropriate dose titration is recommended in these patients. [See CLINICAL PHARMACOLOGY.] Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used.
Patients receiving rosiglitazone in combination with a sulfonylurea may be at risk for hypoglycemia, and a reduction in the dose of the sulfonylurea may be necessary [see DOSAGE AND ADMINISTRATION].
AVANDARYL should be used with caution in patients with edema. In a clinical trial in healthy volunteers who received 8 mg of rosiglitazone once daily for 8 weeks, there was a statistically significant increase in median plasma volume compared to placebo.
Since thiazolidinediones, including rosiglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, AVANDARYL should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure [see BOXED WARNING and PATIENT INFORMATION].
In controlled clinical trials of patients with type 2 diabetes, mild to moderate edema was reported in patients treated with rosiglitazone, and may be dose-related. Patients with ongoing edema were more likely to have adverse events associated with edema if started on combination therapy with insulin and rosiglitazone [see ADVERSE REACTIONS]. The use of AVANDARYL in combination with insulin is not recommended.
Dose-related weight gain was seen with AVANDARYL, rosiglitazone alone, and rosiglitazone together with other hypoglycemic agents (see Table 5). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.
Table 5. Weight Changes (kg) From Baseline at Endpoint During
Clinical Trials [Median (25th, 75th, Percentile)]
|Duration||Control Group||Rosiglitazone 4 mg||Rosiglitazone 8 mg|
|26 weeks||Placebo|| -0.9 (-2.8, 0.9)
N = 210
| 1.0 (-0.9, 3.6)
N = 436
N = 439
|52 weeks||Sulfonylurea|| 2.0 (0, 4.0)
| 2.0 (-0.6, 4.0)
| 2.6 (0, 5.3)
|Rosiglitazone + Control Therapy|
|Duration||Control Group||Rosiglitazone 4 mg||Rosiglitazone 8 mg|
|24-26 weeks||Sulfonylurea|| 0 (-1.0, 1.3)
| 2.2 (0.5, 4.0)
N = 613
|26 weeks||Metformin|| -1.4 (-3.2, 0.2)
| 0.8 (-1.0, 2.6)
|26 weeks||Insulin|| 0.9 (-0.5, 2.7)
| 5.4 (3.4, 7.3)
hi a 4- to 6-year, monotherapy, comparative trial (ADOPT) in patients recently diagnosed with type 2 diabetes not previously treated with antidiabetic medication, the median weight change (25th, 75th percentiles) from baseline at 4 years was 3.5 kg (0.0, 8.1) for rosiglitazone, 2.0 kg (-1.0, 4.8) for glyburide, and -2.4 kg (-5.4, 0.5) for metformin.
In postmarketing experience with rosiglitazone alone or in combination with other hypoglycemic agents, there have been rare reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure [see BOXED WARNING].
With sulfonylureas, including glimepiride, there may be an elevation of liver enzyme levels in rare cases. In isolated instances, impairment of liver function (e.g., with cholestasis and jaundice), as well as hepatitis (which may also lead to liver failure) have been reported.
Liver enzymes should be measured prior to the initiation of therapy with AVANDARYL in all patients and periodically thereafter per the clinical judgment of the healthcare professional. Therapy with AVANDARYL should not be initiated in patients with increased baseline liver enzyme levels (ALT >2.5X upper limit of normal). Patients with mildly elevated liver enzymes (ALT levels ≤2.5X upper limit of normal) at baseline or during therapy with AVANDARYL should be evaluated to determine the cause of the liver enzyme elevation. Initiation of, or continuation of, therapy with AVANDARYL in patients with mild liver enzyme elevations should proceed with caution and include close clinical follow-up, including more frequent liver enzyme monitoring, to determine if the liver enzyme elevations resolve or worsen. If at any time ALT levels increase to >3X the upper limit of normal in patients on therapy with AVANDARYL, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain >3X the upper limit of normal, therapy with AVANDARYL should be discontinued.
If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with AVANDARYL should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.
Macular edema has been reported in postmarketing experience in some diabetic patients who were taking rosiglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but some patients appear to have been diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione. Patients with diabetes should have regular eye exams by an ophthalmologist, per the Standards of Care of the American Diabetes Association. Additionally, any diabetic who reports any kind of visual symptom should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings. [See ADVERSE REACTIONS.]
In a 4- to 6-year comparative trial (ADOPT) of glycemic control with monotherapy in drug-naive patients recently diagnosed with type 2 diabetes mellitus, an increased incidence of bone fracture was noted in female patients taking rosiglitazone. Over the 4- to 6-year period, the incidence of bone fracture in females was 9.3% (60/645) for rosiglitazone versus 3.5% (21/605) for glyburide and 5.1% (30/590) for metformin. This increased incidence was noted after the first year of treatment and persisted during the course of the trial. The majority of the fractures in the women who received rosiglitazone occurred in the upper arm, hand, and foot. These sites of fracture are different from those usually associated with postmenopausal osteoporosis (e.g., hip or spine). Other trials suggest that this risk may also apply to men, although the risk of fracture among women appears higher than that among men. The risk of fracture should be considered in the care of patients treated with rosiglitazone, and attention given to assessing and maintaining bone health according to current standards of care.
Decreases in hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with rosiglitazone [see ADVERSE REACTIONS]. The observed changes may be related to the increased plasma volume observed with treatment with rosiglitazone.
Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because glimepiride, a component of AVANDARYL, belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In post-marketing experience, hemolytic anemia has also been reported in patients receiving sulfonylureas who did not have known G6PD deficiency [see ADVERSE REACTIONS].
Diabetes and Blood Glucose Control
When a patient stabilized on any antidiabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold AVANDARYL and temporarily administer insulin. AVANDARYL may be reinstituted after the acute episode is resolved.
Therapy with rosiglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking rosiglitazone [see Use in Specific Populations]. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical trials; therefore the frequency of this occurrence is not known.
Although hormonal imbalance has been seen in preclinical studies [see Nonclinical Toxicology], the clinical significance of this finding is not known. If unexpected menstrual dysfunction occurs, the benefits of continued therapy with AVANDARYL should be reviewed.
Patient Counseling Information
See Medication Guide.
There are multiple medications available to treat type 2 diabetes. The benefits and risks of each available diabetes medication should be taken into account when choosing a particular diabetes medication for a given patient.
Patient should fully understand the risks and benefits of AVANDARYL. AVANDARYL should only be taken by adults with type 2 diabetes who are already taking rosiglitazone, or who are not already taking rosiglitazone and are unable to achieve adequate glycemic control on other diabetes medications, and, in consultation with their healthcare provider, have decided not to take pioglitazone (ACTOS) or pioglitazone-containing medications (ACTOPLUS MET, ACTOPLUS MET XR, DUETACT) for medical reasons. Inform patients that they must be enrolled in the AVANDIA-Rosiglitazone Medicines Access Program in order to receive AVANDARYL.
Patients should be informed of the following:
- AVANDARYL is not recommended in patients with symptomatic heart failure.
- Results of a set of clinical trials suggest that treatment with AVANDARYL is associated with an increased risk for myocardial infarction (heart attack), especially in patients taking insulin. Clinical trials have not shown any difference between rosiglitazone and comparator medications in overall mortality or CV-related mortality.
- AVANDARYL is not recommended for patients who are taking insulin.
- Management of type 2 diabetes should include diet control. Caloric restriction, weight loss, and exercise are essential for the proper treatment of the diabetic patient because they help improve insulin sensitivity. This is important not only in the primary treatment of type 2 diabetes, but also in maintaining the efficacy of drug therapy.
- It is important to adhere to dietary instructions and to regularly have blood glucose and glycosylated hemoglobin (HbAlc) tested. It can take 2 weeks to see a reduction in blood glucose and 2 to 3 months to see the full effect of AVANDARYL.
- The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members.
- Blood will be drawn to check their liver function prior to the start of therapy and periodically thereafter per the clinical judgment of the healthcare professional. Patients with unexplained symptoms of nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine should immediately report these symptoms to their physician.
- Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on AVANDARYL should immediately report these symptoms to their physician.
- AVANDARYL should be taken with the first meal of the day.
- Therapy with rosiglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking AVANDARYL. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical trials so the frequency of this occurrence is not known.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No animal studies have been conducted with AVANDARYL. The following data are based on findings in studies performed with rosiglitazone or glimepiride alone.
Carcinogenesis: A 2-year carcinogenicity study was conducted in Charles River CD-I mice at doses of 0.4, 1.5, and 6 mg/kg/day in the diet (highest dose equivalent to approximately 12 times human AUC at the maximum recommended human daily dose). Sprague-Dawley rats were dosed for 2 years by oral gavage at doses of 0.05 mg/kg/day, 0.3 mg/kg/day, and 2 mg/kg/day (highest dose equivalent to approximately 10 and 20 times human AUC at the maximum recommended human daily dose for male and female rats, respectively).
Rosiglitazone was not carcinogenic in the mouse. There was an increase in incidence of adipose hyperplasia in the mouse at doses ≥1.5 mg/kg/day (approximately 2 times human AUC at the maximum recommended human daily dose). In rats, there was a significant increase in the incidence of benign adipose tissue tumors (lipomas) at doses ≥0.3 mg/kg/day (approximately 2 times human AUC at the maximum recommended human daily dose). These proliferative changes in both species are considered due to the persistent pharmacological overstimulation of adipose tissue.
Mutagenesis: Rosiglitazone was not mutagenic or clastogenic in the in vitro bacterial assays for gene mutation, the in vitro chromosome aberration test in human lymphocytes, the in vivo mouse micronucleus test, and the in vivo/in vitro rat UDS assay. There was a small (about 2-fold) increase in mutation in the in vitro mouse lymphoma assay in the presence of metabolic activation.
Impairment of Fertility: Rosiglitazone had no effects on mating or fertility of male rats given up to 40 mg/kg/day (approximately 116 times human AUC at the maximum recommended human daily dose). Rosiglitazone altered estrous cyclicity (2 mg/kg/day) and reduced fertility (40 mg/kg/day) of female rats in association with lower plasma levels of progesterone and estradiol (approximately 20 and 200 times human AUC at the maximum recommended human daily dose, respectively). No such effects were noted at 0.2 mg/kg/day (approximately 3 times human AUC at the maximum recommended human daily dose). In juvenile rats dosed from 27 days of age through to sexual maturity (at up to 40 mg/kg/day), there was no effect on male reproductive performance, or on estrous cyclicity, mating performance or pregnancy incidence in females (approximately 68 times human AUC at the maximum recommended daily dose). In monkeys, rosiglitazone (0.6 and 4.6 mg/kg/day; approximately 3 and 15 times human AUC at the maximum recommended human daily dose, respectively) diminished the follicular phase rise in serum estradiol with consequential reduction in the luteinizing hormone surge, lower luteal phase progesterone levels, and amenorrhea. The mechanism for these effects appears to be direct inhibition of ovarian steroidogenesis.
Carcinogenesis: Studies in rats at doses of up to 5,000 parts per million (ppm) in complete feed (approximately 340 times the maximum recommended human dose, based on surface area) for 30 months showed no evidence of carcinogenesis. In mice, administration of glimepiride for 24 months resulted in an increase in benign pancreatic adenoma formation which was dose-related and is thought to be the result of chronic pancreatic stimulation. The no-effect dose for adenoma formation in mice in this study was 320 ppm in complete feed, or 46 to 54 mg/kg body weight/day. This is about 35 times the maximum human recommended dose based on surface area.
Mutagenesis: Glimepiride was non-mutagenic in a battery of in vitro and in vivo mutagenicity studies (Ames test, somatic cell mutation, chromosomal aberration, unscheduled DNA synthesis, mouse micronucleus test).
Impairment of Fertility: There was no effect of glimepiride on male mouse fertility in animals exposed up to 2,500 mg/kg body weight (>1,700 times the maximum recommended human dose based on surface area). Glimepiride had no effect on the fertility of male and female rats administered up to 4,000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area).
Use In Specific Populations
Pregnancy Category C
All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Careful monitoring of glucose control is essential in such patients. Most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible. AVANDARYL should not be used during pregnancy.
Human Data: There are no adequate and well-controlled trials with AVANDARYL or its individual components in pregnant women. Rosiglitazone has been reported to cross the human placenta and be detectable in fetal tissue. The clinical significance of these findings is unknown.
Animal Studies: No animal studies have been conducted with AVANDARYL. The following data are based on findings in studies performed with rosiglitazone or glimepiride individually.
Rosiglitazone: There was no effect on implantation or the embryo with rosiglitazone treatment during early pregnancy in rats, but treatment during mid-late gestation was associated with fetal death and growth retardation in both rats and rabbits. Teratogenicity was not observed at doses up to 3 mg/kg in rats and 100 mg/kg in rabbits (approximately 20 and 75 times human AUC at the maximum recommended human daily dose, respectively). Rosiglitazone caused placental pathology in rats (3 mg/kg/day). Treatment of rats during gestation through lactation reduced litter size, neonatal viability, and postnatal growth, with growth retardation reversible after puberty. For effects on the placenta, embryo/fetus, and offspring, the no-effect dose was 0.2 mg/kg/day in rats and 15 mg/kg/day in rabbits. These no-effect levels are approximately 4 times human AUC at the maximum recommended human daily dose. Rosiglitazone reduced the number of uterine implantations and live offspring when juvenile female rats were treated at 40 mg/kg/day from 27 days of age through to sexual maturity (approximately 68 times human AUC at the maximum recommended daily dose). The no-effect level was 2 mg/kg/day (approximately 4 times human AUC at the maximum recommended daily dose). There was no effect on pre- or post-natal survival or growth.
Glimepiride: Glimepiride did not produce teratogenic effects in rats exposed orally up to 4,000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area) or in rabbits exposed up to 32 mg/kg body weight (approximately 60 times the maximum recommended human dose based on surface area). Glimepiride has been shown to be associated with intrauterine fetal death in rats when given in doses as low as 50 times the human dose based on surface area and in rabbits when given in doses as low as 0.1 times the human dose based on surface area. This fetotoxicity, observed only at doses inducing maternal hypoglycemia, has been similarly noted with other sulfonylureas, and is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride.
In some studies in rats, offspring of dams exposed to high levels of glimepiride during pregnancy and lactation developed skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. Significant concentrations of glimepiride were observed in the serum and breast milk of the dams as well as in the serum of the pups. These skeletal deformations were determined to be the result of nursing from mothers exposed to glimepiride. Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives.
Labor and Delivery
The effect of AVANDARYL or its components on labor and delivery in humans is unknown.
No trials have been conducted with AVANDARYL. It is not known whether rosiglitazone or glimepiride is excreted in human milk. Because many drugs are excreted in human milk, AVANDARYL should not be administered to a nursing woman.
Rosiglitazone: Drug-related material was detected in milk from lactating rats.
Glimepiride: In rat reproduction studies, significant concentrations of glimepiride were observed in the serum and breast milk of the dams, as well as in the serum of the pups. Although it is not known whether glimepiride is excreted in human milk, other sulfonylureas are excreted in human milk.
Safety and effectiveness of AVANDARYL in pediatric patients have not been established. AVANDARYL and its components, rosiglitazone and glimepiride, are not indicated for use in pediatric patients.
Rosiglitazone: Results of the population pharmacokinetic analysis showed that age does not significantly affect the pharmacokinetics of rosiglitazone [see CLINICAL PHARMACOLOGY]. Therefore, no dosage adjustments are required for the elderly. In controlled clinical trials, no overall differences in safety and effectiveness between older (≥65 years) and younger (<65 years) patients were observed.
Glimepiride: In US clinical trials of glimepiride, 608 of 1,986 patients were 65 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
Comparison of glimepiride pharmacokinetics in type 2 diabetes patients ≤65 years (N = 49) and those >65 years (N = 42) was performed in a trial using a dosing regimen of 6 mg daily. There were no significant differences in glimepiride pharmacokinetics between the 2 age groups [see CLINICAL PHARMACOLOGY].
The drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Elderly patients are particularly susceptible to hypoglycemic action of glucose-lowering drugs. In elderly, debilitated, or malnourished patients, or in patients with renal, hepatic or adrenal insufficiency, the starting dose, dose increments, and maintenance dosage should be conservative based upon blood glucose levels prior to and after initiation of treatment to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
1. Food and Drug Administration Briefing Document. Joint meeting of the Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees. July 13-14, 2010.
2. Winkelmayer WC, et al. Comparison of cardiovascular outcomes in elderly patients with diabetes who initiated rosiglitazone vs pioglitazone therapy. Arch Intern Med 2008;168(21):2368-2375.
3. Juurlink DN, et al. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. BMJ 2009; 339.
4. Graham DJ, et al. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly medicare patients treated with rosiglitazone or pioglitazone. JAMA 2010;304:411-418.
5. Wertz DA, et al. Risk of cardiovascular events and all-cause mortality in patients with Thiazolidinediones in a managed-care population. Circ Cardiovasc Qual Outcomes 2010;3: 538-545.
6. URbAM Inal Investigators, brrect or rosightazone on the frequency or diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2W6;36S: 1096-1105.
7. Kahn S, et al. Glycemic durability of rosiglitazone, metformin or glyburide monotherapy. New England Journal of Medicine 2006, 355:2427-2443.
8. Home P, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicenter, randomized, open-label trial. Lancet 2009, 373:2125-35.
9. Dormandy J et al. Secondary prevention of macro vascular events in patients with type 2 diabetes in the PROactive study (Prospective Pioglitazone Clinical Trial in Macrovascular Events): a randomized controlled trial. Lancet 2005, 366:1279-89.
10. Bilik D, et al. Thiazolidinediones, cardiovascular disease and cardiovascular mortality: translating research into action for diabetes (TRIAD). Pharmocoepidemiol Drug Saf 20lO; 19:715-721.
Last reviewed on RxList: 12/5/2011
This monograph has been modified to include the generic and brand name in many instances.
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